Genetic instability plays a prominent role in biology and medicine. It is associated with diverse biological processes such as aging, developmental defects and tumorigenesis. At the same time, induction of genetic instability with ionizing radiation is used to treat cancer. Here, we report that genetic instability also has a profound effect on protein quality control. HSP90 is a chaperone that folds a subset of the proteome called clients, which are composed of proteins important for signaling, such as kinases, steroid receptors, transcription factors and enzymes. DNA-PK is one of the kinases that phosphorylates HSP90 and regulates its activity. We found that upon phosphorylation by DNA-PK, HSP90a releases many of its substrates. Among the 40 kinases that we tested, we found that 40% of them were released by DNA-PK.On the other hand, the rapid release prevents the proper folding of some clients such as the cystic fibrosis transmembrane conductance regulator and glucocorticoid receptor. These findings indicate that DNA-PK mediates an unexpected coordination between protein quality control and genetic integrity.